Beschreibung:
We study neurotransmitter clearance by low‐affinity, high‐capacity uptake‐2 transporters. This family includes plasma membrane monoamine transporter (PMAT) and three organic cation transporter isoforms (OCT1‐3). We have shown uptake‐2 transporters limit the effectiveness of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine. Discerning the transporter type(s) involved is restricted by the lack of highly selective ligands. This project examines the pharmacological characteristics of novel uptake‐2 compounds.Activity of ANSTO analogs, structurally based on the non‐selective inhibitor decynium 22 (D22), was tested in human OCT3‐HEK cells. Ligand competitions of [3H]MPP+ uptake were measured in whole, attached cells. Compared to D22, dose‐responses of ANSTO compounds shifted 1‐ or 2 log‐rightward, indicating reduced potency to inhibit OCT3 mediated [3H]MPP+ uptake. ANSTO analogs displayed similar potencies to corticosterone and may have higher selectivity at alternate uptake 2 subtypes.[3H]MPP+ Uptake Competition in hOCT3‐HEK CellsCOMPOUNDSIC50 (µM)ANSTO 3013.9ANSTO 3022.5ANSTO 3030.76ANSTO 3040.71ANSTO 3050.41ANSTO 3060.71ANSTO 3071.2Corticosterone1.3Decynium 220.072Analyses in PMAT over‐expressing cells are ongoing. Analogs and SSRI competitions will be measured in brain preparations from OCT3 knockout & PMAT knockout mice for physiological comparisons to our findings in cells. These studies will reveal more about the pharmacological profile of these novel compounds for their potential therapeutic application to treat disorders with neurotransmitter dysregulation, such as depression and drug abuse.Supported by NIH MH093320 and NRSA T32DA031115.